4,4 -disubstituted-prolines

For related syntheses of /mns,-4-substituted or 3,4-disubstituted proline derivatives see refs 101-104. 

In the search of new methodologies for the asymmetric synthesis of nonproteinogenic amino acids, 8-methyl-4,8a-diphenyltetrahydro-17/-pyrrolo[2.1 -r l, 4 oxazinc-l, 6(7//)-dionc 62, obtained as described in Scheme 24 (Section 11.11.7.3), was selectively reduced at the lactam carbonyl with BH3 and further opened by hydrogenolysis to give syn-disubstituted proline derivative 64 in 95% yield <1997SL935> (Scheme 6). It is noteworthy that hydrogenolysis did not affect the benzylic position of bicyclic compound 63. 

Scheme 41 A double N-a-methoxylation for the synthesis of the a.a -disubstituted proline Anatoxin.

The combined Birch reduction alkylation of chiral, enantiomerically pure aroyl amides of 2-pyrrolidinemethanol (prolinol) or 2-pyrrolidinecarboxylic acid (proline) gives chiral, non-racemic, 1,1-disubstituted 2,5-cyclohexadienes 1 or 2-cyclohexenes 2, respectively, in high diastereomeric ratios. These reactions are useful for the preparation of valuable chiral synthetic intermediates 3 25 29-31-36. 

In the asymmetric synthesis of 4,4-disubstituted cyclohexenones of the type (132) it was possible to raise the optical yield to a maximum of 54 % by varying the structures of the carbonyl compounds 150) and of the proline derivatives (131)151). 

Terashima et al. 231) reported an asymmetric halolactonization reaction. This highly stereoselective reaction permits the synthesis of intermediates for the preparation of chiral a,a-disubstituted a-hydroxycarboxylic acids (227)231c), a-hydroxyketones (228) 231c), functionalized epoxides (229) 231d,e) and natural products 231h,j). Only amino acids have so far been used as a source of the chiral information in the asymmetric halolactonization reaction. Again, the best results have been obtained by using cyclic imino acid enantiomers, namely proline. 

The aims of inserting a thiazolidine-4-carboxylic acid (4-thiaproline, Thz, 11) residue into peptide chains are similar to those discussed for the 4-oxaproline analogue in Section 9.2.3.4.I. Thiazolidine-4-carboxylic acid (11), particularly when disubstituted at the C5 position of the proline ring, can act as a cysteine precursor and concomitantly as an amide backbone protecting group (see Section 23.2.4). Its solubilizing properties derive from its preference for the cis configuration of the Xaa-Thz bond. 169-172 ... 

Note 4-Thiaproline is also named as pseudoproline, Cys(WPro), 169 whereby the related disubstituted derivatives at the C5 position of the proline ring are defined as... 

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

In the synthesis of l,2,5-triazepine-l,5-diones, which are expected to mimic the structural features of or-peptidyl prolin-amides, the preparation of N2,N3-disubstituted derivatives 213a from the reaction of (Z)-alanine with the N2-substituted triazepines 213 resulted in lower yields. It has been reported that these fused triazepinediones could be elaborated to give constrained rir-peptidyl proline peptide mimetics of defined stereochemistry and sequence <1997J(P1)2297>. 

Disubstituted cyclopentane-1,3-diones and cyclohexane-1,3-diones were used as substrates. After formation of the aldol adducts subsequent intramolecular dehydration furnished products of types 94 and 96. The asymmetric intramolecular aldol reaction proceeds with a broad variety of natural amino acids as organocata-lysts. Among these L-proline was usually found to be the most versatile. For example, conversion of the 2,2-disubstituted cyclopentane-1,3-dione 93 in the presence of L-proline gave the desired product 94 in 86.6% yield and with enantioselectivity of 84% ee [97]. This example and a related reaction with a 2,2-disubstituted cyclohexane-1,3-dione 95 are shown in Scheme 6.42. Chiral induction depends... 

A highly diastereo- and enantioselective synthesis of trans-l,2-disubstituted cyclohexanes by means of the first direct catalytic asymmetric 6-enolexo aldoliza-tion has been developed very recently by the List group [120] (previously only 6-enolendo aldolizations had been reported). Dialdehydes were usually used as starting materials and proline was a very effident catalyst for this reaction also. A selected example of this 6-enolexo-aldolization is given in Scheme 6.50 in this... 

The authors of [138] propose an one-pot method for the production of disubstituted phosphonous acids that are derivatives of proline. 

Scheme 2.28 The direct enantioselective a-amination of a,a-disubstituted aldehydes catalyzed by L-proline, and further transformations to optically active oxazolidinones.

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

Asymmetric rearrangement of cyclohexene oxide. Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyOpyrrolidines prepared from (S)-proline are almost as stereoselective. ... 

Proline has long been known to help a peptide adopt a reverse-turn conformation (71). For example, the classic type VI turn was defined as having a cm-amide bond between residues i + 1 and i + 2, which proline facilitates in the i + 2 position due to its disubstituted amide nitrogen. The sequence d-Pro-l-Pro in particular has been found to adopt a reverse-turn conformation (84-86) and alternating d/l amino acid sequences facilitate cycli-zation of small peptides as discussed in a review of cyclization of peptides and depsipeptides by Davies (87). Particular difficulties in cyclization of linear tetrapeptides containing residues of the same chirality have been found (88). Durani has discussed designing small folded proteins based on an alphabet of d- and L-amino acids (89). 

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